Electrostatic loading of drugs on implantable medical devices

ABSTRACT

A method for electrostatic loading of drugs on an implantable medical device is disclosed.

CROSS REFERENCE

This is a divisional of U.S. application Ser. No. 10/306,648 filed onNov. 26, 2002.

BACKGROUND

This invention relates to an apparatus and method for electrostaticloading of a drug onto an implantable medical device such as a stent.

FIG. 1 illustrates a stent 10 having a conventional design of struts 12interconnected by connecting elements 14. Struts 12 and connectingelements 14 are separated by gaps 16. Stent 10 is generally cylindricaland radially compressible. Compressible embodiments of stent 10 can beballoon expandable or self-expandable. Although stents work wellmechanically, the chronic issues of restenosis and, to a lesser extent,thrombosis remain a significant clinical problem. These events areaffected and made worse by the degree of injury and the hemodynamicdisturbance caused by the stent. In order to more effectively treatthese conditions, pharmacological therapy can be used in conjunctionwith stent therapy. Maintaining the necessary drug concentration at thelesion site for the necessary period of time remains a challenge,however. This can be done with brute force methods using oral orintravenous administration but the issues of systemic toxicity and sideeffects arise. Therefore, a preferred route can be achieved by localdelivery of drug from the stent itself.

Being made of metal, plain stents are not useful for drug delivery. Toserve as a drug reservoir, a coating, usually of a polymer, is appliedby dipping or spraying the stent. A solution of a polymer dissolved in asolvent and a therapeutic substance added thereto is applied to thestent and the solvent is allowed to evaporate. A polymeric coatingimpregnated with a therapeutic substance then remains on the surface ofthe stent.

This manufacturing process can consume large quantities of solvent andprocess time. This process can also reduce the capability of batchprocessing (e.g., processing large stent quantities in single productionruns) since each stent is individually sprayed with or dipped into thecoating solution. Accordingly, a stent coating process is desired thatreduces waste solvent and process time and can facilitate batchprocessing.

SUMMARY

A method of depositing a therapeutic substance on a stent is disclosedcomprising ionizing a therapeutic substance; applying an electricalcharge to a stent; and exposing the electrically charged stent to theionized therapeutic substance. The therapeutic substance can be ionizedby introducing a gas in a pressure chamber; applying pulsed bias voltageto a mesh tube surrounding the stent; applying RF power to a coilsurrounding the mesh tube to produce electrons; and introducing thetherapeutic substance into the chamber. The therapeutic substance can beintroduced in bursts. The bias voltage applied to the mesh tube and theRF power can be turned off during the application of the electricalcharge to the stent. The stent can be pre-coated with a primer layer.

A method for depositing a drug on a stent is disclosed comprisingpositioning a stent on a mandrel within a chamber, the mandrel beingsurrounded by a mesh tube and a coil; introducing a gas into thechamber; applying an RF power to the coil to produce electrons; applyingan electrical charge to the mesh tube to collect the electrons aroundthe stent; applying an electrical charge to the stent while terminatingthe application of the RF power to the coil and the electrical charge tothe mesh tube; and supplying a drug into the chamber for ionizing thedrug so that the drug is attracted to the stent. The drug can besupplied into the chamber by an inert carrier gas.

A method for depositing a drug onto a stent is disclosed comprisingdirecting a drug towards a stent and operating a system including a coilsurrounding the stent for charging the drug so that the drug isattracted to and deposited onto the stent. An electrical charge can beapplied to the stent. In some embodiments, the system additionallyincludes a collecting member next to the stent, the collecting membercapable of receiving a charge for collecting charged particles aroundthe stent.

A method for depositing a drug onto a stent is disclosed comprisingdirecting a charged drug towards a stent and operating a systemincluding a collecting member positioned adjacent to the stent forcollecting the charged drug around the stent. In some embodiments, thecollecting member can be a mesh tube surrounding the stent. The methodcan include applying a charge to the stent and/or the collecting member.

DESCRIPTION OF THE DRAWINGS

FIG. 1 illustrates a conventional stent.

FIG. 2 is a schematic illustration of an embodiment of the coatingsystem.

FIG. 3 is one embodiment of the mesh tube in which a stent can be placedsurrounded by an RF coil.

FIG. 4 is one embodiment of the stent, mesh tube, and RF coil inside ofa pressure chamber.

DETAILED DESCRIPTION

FIG. 2 illustrates an embodiment of an agent loading apparatus 18, whichincludes a chamber 20 housing a stent support apparatus or mandrel 22for supporting stent 10. Mandrel 22 is placed in electrical contact withan electrical feed 24 within chamber 20. Any suitable chamber 20 can beused, for example chambers that have electrical feed 24 mounted on aKF-40 flange (MDC, Hayward, Calif.). In one embodiment, as illustratedin FIG. 3, a grid or mesh tube 26 can circumscribe mandrel 22 and stent10. Grid 26 can extract the electrons within the mesh tube and increasethe uniformity of the coating surface. Grid 26 can have a tube diameterDG of about 2.5 cm and a thickness of about 0.1 mm. The surface area ofthe cylinder formed by grid or mesh tube 26 can be about 90% open voidsand about 10% mesh. Mesh tube 26 can be connected to a second electricalfeed, or can share electrical feed 24 with mandrel 22. An RF coil 28circumscribes grid 26. The diameter D_(c) of the coil can be about 5.1cm.

Referring again to FIG. 2, a gas feed line 30 is in fluid communicationwith chamber 20 and a loading cavity 32, which in turn is in fluidcommunication with chamber 20. Loading cavity 32 holds the drugs inpowder form. Closeable gates or valves 34 can be used to control theflow of the gas. A pump 36 can also be in fluid communication withchamber 20. Pump 36 can be a turbo pump, a mechanical rough pump, or acryo pump. A particulate trap 38 can be disposed between pump 36 andchamber 20. One example of trap 38 is a Coaxial 4-line/Roughing Trap(from Varian Inc., Tempe, Ariz.) that attaches to a KF-40 flange. Trap38 can minimize contamination in the exhaust from reaching pump 36. Trap38 can filter particles from of up to, for example 10 microns (0.4 mils)in diameter.

One of ordinary skill in the art can understand that a plurality ofstents 10 can be loaded onto mandrels 22 placed within chamber 20 in agrid-like or similar configuration to enable batch processing of stents10. Additionally the medical device need not be limited to stents and avariety of other medical devices which need to be modified to delivery adrug can also be used.

A gas such as argon is introduced into chamber 20 and the pressure ismaintained at about 50 to 100 mTorr. A pulsed bias of up to, forexample, 50 V is applied to grid 26 while an RF power of, for example,100 W at a frequency of 13.56 MHz is applied to initiate formation ofelectrons. Electrons are produced in chamber 20 while grid 26 collectsthe electrons around stent 10. Loading cavity 32 holds the drug inpowder form having particles from about 1 micron (0.04 mils) to about 5microns (0.2 mils) in diameter. The drug should be electrophilic tofacilitate charging of the particles.

A carrier gas can then flow from gas feed line 30 through loading cavity32, carrying the drug through gate 34 and into chamber 20. The gasshould be inert to the biological properties of the drug. For example,gasses of helium, nitrogen, argon, neon, xenon, krypton, or combinationsthereof can be used as the carrier. The drug is supplied in bursts, suchas in 500 millisecond bursts into chamber 20 which, in effect, can raisethe pressure in the chamber up to for example, 500 mTorr. The gas can beintroduced at any temperature from about absolute zero to an upper limittemperature of the drug. The upper limit temperature of the drug isdefined as the temperature above which the active agent begins toundergo substantial changes that permanently alter its biologicalefficacy. The upper limit temperature can be determined by one havingordinary skill in the art for each respective drug. Gate 34 can beopened and closed manually, or gate 34 can be closed automatically, forexample when the pressure across gate 34 drops below a pre-determinedlevel entered into a gate controller. The pulsed bias applied to grid 26and RF power are tuned off and a pulsed bias is applied to stent 10 viamandrel 22, for example up to about 50 KV. As a result, the ionized drugis deposited on stent 10.

Stent 10 can be pre-coated with an appropriate coating, for example acarbon pre-coating or deposits or a primer polymer layer, to help adherethe substance to stent 10. The particles can then be compacted onto thesurface of stent 10 or on the primer layer. It is believed that thiscoating method may produce a coating with a thickness from about 0.25microns (0.0098 mils) to about 3 microns (0.1 mils) with a uniformitywith less than about 5% variation in thickness.

Agent loading apparatus 18 and the coating method described herein canbe used in conjunction with rotary atomizer or spray chillingapparatuses that coat stent 10 with polymers or polymer and agentcombinations. Agent loading apparatus 18 can load an agent onto stent 10before stent 10 is coated with a polymer or polymer and agent topcoatingby a different process. The use of the inventive process and acomplementary process can minimize the use of solvents for the agentapplication processes and enable the coating of large quantities ofstents 10 in single batches.

The substance loaded onto the stent can be, for example, any drugcapable of inhibiting abnormal or inappropriate migration and/orproliferation of smooth muscle cells for the prevention or inhibition ofrestenosis. The drug can also be capable of exerting a therapeutic orprophylactic effect such as for example enhancing wound healing in avascular site or improving the structural and elastic properties of thevascular site.

While particular embodiments of the present invention have been shownand described, it will be obvious to those skilled in the art thatchanges and modifications can be made without departing from thisinvention in its broader aspects. Therefore, the appended claims are toencompass within their scope all such changes, modifications, andcombinations as fall within the true spirit and scope of the invention.

1. A method of depositing a therapeutic substance on a stent,comprising: ionizing a therapeutic substance; applying an electricalcharge to a stent; and exposing the electrically charged stent to theionized therapeutic substance.
 2. The method of claim 1, whereintherapeutic substance is ionized by introducing a gas in a pressurechamber; applying pulsed bias voltage to a mesh tube surrounding thestent; applying RF power to a coil surrounding the mesh tube to produceelectrons; and introducing the therapeutic into the chamber.
 3. Themethod of claim 2, wherein the therapeutic substance is introduced inbursts.
 4. The method of claim 2; wherein the bias voltage applied tothe mesh tube and the RF power are turned off during the application ofthe electrical charge to the stent.
 5. The method of claim 1, whereinthe stent is pre-coated with a primer layer.
 6. A method for depositinga drug on a stent, comprising: positioning a stent on a mandrel within achamber, the mandrel being surrounded by a mesh tube and a coil;introducing a gas into the chamber; applying an RF power to the coil toproduce electrons; applying an electrical charge to the mesh tube tocollect the electrons around the stent; applying an electrical charge tothe stent while terminating the application of the RF power to the coiland the electrical charge to the mesh tube; and supplying a drug intothe chamber for ionizing the drug so that the drug is attracted to thestent.
 7. The method of claim 6, wherein the drug is supplied into thechamber by an inert carrier gas.
 8. A method for depositing a drug ontoa stent, comprising: directing a drug towards a stent; and operating asystem including a coil surrounding the stent for charging the drug sothat the drug is attracted to and deposited onto the stent.
 9. Themethod of claim 8, additionally comprising applying an electrical chargeto the stent.
 10. The method of claim 8, wherein the system additionallyincludes a collecting member next to the stent for collecting chargedparticles around the stent.
 11. The method of claim 10, wherein thecollecting member is located between the stent and the coil.
 12. Amethod for depositing a drug onto a stent, comprising: directing acharged drug towards a stent; and operating a system including acollecting member positioned adjacent to the stent for collecting thecharged drug around the stent.
 13. The method of claim 12, wherein thecollecting member is a mesh tube surrounding the stent.
 14. The methodof claim 12, additionally comprising applying a charge to the stentand/or the collecting member.